Teaching

Research Areas

i. Fanconi Anemia and the Cellular DNA Damage Response

Fanconi anemia (FA) is a rare genetic disease characterized by developmental defects, progressive bone marrow failure, and increased susceptibility to cancer. The incidence of FA is estimated to be between 1 in 200,000-400,000 live births. To date, 15 FA genes have been identified: FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, and FANCP/SLX4. The protein products of these genes are thought to act cooperatively in a pathway, the FA-BRCA pathway, to repair DNA damage and prevent cellular transformation. The study of FA is highly significant for several reasons. First and foremost, FA is a devastating and life-threatening disease that affects several hundred US families alone. Therapeutic options for FA are extremely limited. A greater understanding of the molecular basis of FA will ultimately lead to improved diagnostic and therapeutic approaches to FA, directly benefiting FA patients and their families. Second, as FA is unequivocally linked to both hematologic and non-hematologic cancer susceptibility, our findings will provide important mechanistic insight in to the molecular origins of cancer susceptibility in the general (non-FA) population.

ii. Regulation of the Mono-Ubiquitination of the FANCD2 and FANCI proteins

A central step in the regulation of the activation of the FA-BRCA pathway is the mono-ubiquitination of the FANCD2 (and FANCI) proteins. How this important post-translational modification step is regulated is poorly understood. Furthermore, the role of mono-ubiquitinated FANCD2 in the DNA damage response is unknown. We use biochemical and genetic methods to address these two important questions in FA biology.

iii. Understanding the Role of the FA-BRCA Pathway in the Suppression of Genomic Copy Number Variation

Copy number variation, or copy number change, which refers to deletions or duplications of tens of thousands to millions of nucleotides, is both a normal feature of genetic variation and a major contributor to genetic disease. The mechanisms by which copy number change occurs and the cellular pathways that suppress copy number change are largely unknown. We have recently uncovered an important role for the FA-BRCA pathway in the suppression of de novo copy number change, and are using multiple approaches to further characterize this function.